Non-invasive characterization of tumor response to protein kinase inhibitor therapy by PET imaging

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The aim of this proposal is to characterize tumor response to braf and MEK inhibitor therapy and tumor metabolism in vitro and in vivo. One of the two aims of this proposal is to investigate the interaction between targeted therapy drugs and GLUT-1 (3) expression and F-18-FDG uptake in thyroid cancer, a tumor entity that has a high frequency of braf mutations. In contrast to malignant melanoma thyroid cancers are frequently resistant to braf inhibition. The resistance mechanism involves overexpression of the growth factor heregulin which stimulates HER3 receptors. We want to determine the GLUT-1/GLUT-3 expression in the cell membrane and in cytosol in tumor cell culture in case of therapy with vemurafenib and lapatinib (single- and combination therapy). In the next step we want to evaluate the GLUT-1 (3) expression in case of therapy with vemurafenib and lapatinib (single- and combination therapy) for several time points and then to evaluate the activity of the key enzymes of glycolysis during therapy and comparison with GLUT-1 (3) expression. The last step is to implant the tumor cell culture into mice and to evaluate the effects of the single and combination inhibitor therapy with FDG PET in vivo.The second aim of this proposal is to investigate the inverse relationship of iodine- and FDG storage, the so called flip-flop-phenomenon, in thyroid cancer. Recent clinical studies have indicated that treatment with selumetinib can dramatically increase radioiodine uptake of metastatic thyroid cancer. We will use cell lines to investigate the flip flop-phenomenon using a RAF-inhibitor vemurafenib and the MEK inhibitor selumetinib. Is there a relationship between low iodine and high FDG storage and vice versa? And more interestingly, is there a time slot in which the cells store maximum iodine during the therapy with BRAF inhibitors? Implanting the thyroid tumor cell lines into mice models to investigate observed results in vivo